Histone H1 has seven variants in human somatic
cells and contributes to chromatin compaction and
transcriptional regulation. Knock-down (KD) of each
H1 variant in breast cancer cells results in altered
gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being
most deleterious. Here we show combined depletion
of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated
genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates
to repress ISG promoters, IFN activation upon H1.2
and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid
receptors and IFN synthesis, and without changes
in histone modifications at induced ISG promoters.
H1.2 and H1.4 co-KD also promotes the appearance
of accessibility sites genome wide and, particularly,
at satellites and other repeats. The IFN response may
be triggered by the expression of noncoding RNA
generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an
unspecific IFN response.